In mammals, regeneration of injured tissues and limbs is largely limited by an irreversible differentiation process (see, e.g., Carlson, Dev. Dyn. 226(2):167-81 (2003)). As a consequence, stem cells, in particular embryonic stem cells (ESCs) which can be expanded indefinitely and are pluripotent or multipotent, have attracted considerable attention as a therapeutic approach to the damage caused by cardiovascular disease, neurodegenerative disease and aging (see, e.g., Committee on the Biological and Biomedical Applications of Stem Cell Research, Stem Cells and the Future of Regenerative Medicine 2002, the National Academies Press, Washington, D.C.). However the use of stem cells in cell replacement therapy remains problematic for a number of reasons, including the lack of a reliable source for stem cells. For example, multipotent human mesenchymal stem cells (MSC) may be isolated from the bone marrow; a large amount of donor bone marrow is required to obtain sufficient quantities of stem cells for most therapeutic or research applications.
The ability to dedifferentiate or reverse lineage-committed cells to multipotent progenitor cells (i.e. multipotent stem cells) overcome many of these obstacles. With an efficient dedifferentiation process, it is conceivable that healthy, abundant and easily accessible adult cells could be used to generate different types of functional cells for repair of damaged tissues. Moreover, recent studies of the plasticity of murine myotubes and other cells derived from adult tissues suggest that dedifferentiation may be possible in mammalian system (see, e.g., Odelberg et al., Cell 103:1099-1109 (2000); McGann et al., Proc. Natl. Acad. Sci. USA 98:13699-13704 (2001); and Tsai et al. Developmental Cell 2:707-712 (2002)). However, in contrast to the differentiation process, compositions and methods for the control and study of dedifferentiation are lacking.
Cell-based phenotypic assays and, more recently, pathway screens of synthetic small molecules and natural products have historically provided very useful chemical probes of complex cellular processes (see, e.g., White, D. J. G. Ed., Proceedings of an International Conference on Cyclosporin A (Elsevier, Amsterdam, 1982), 5-19). The identification of small molecules which induce dedifferentiation of mammalian somatic cells should help to elucidate the molecular mechanism of this phenomenon, and may ultimately allow in vivo tissue regeneration.
Thus, there is a need in the art for compositions and methods for inducing dedifferentiation of lineage committed mammalian cells into multipotent or pluripotent stem cells. The present invention satisfies these and other needs.